Authors' reply

The letter of M.W. Agelink and coworkers adds important aspects to our paper [1]. We discussed several shortcomings of our retrospective study. One of these is the co-medication with benzodiazepine and SSRIs. As different authors underline, SSRIs [4] and lorazepam [6] influence the HRV significantly less than drugs with anticholinergic effects and are a very common co-medication in schizophrenic patients. Excluding these patients stresses the naturalistic approach.

We also discussed the arbitrary cutoff of 3.2 % of CV. The cutoff was highly specific but not very sensitive for the clozapine serum concentration. HRV parameters, especially the CV, are very informative about high clozapine concentrations, e. g., in the case of intoxication. Our data are in accordance with data of other anticholinergic drugs [5]. The decrease of HRV strongly suggests an overdose of TCAs (e. g., in amitriptyline delirium) and clozapine [3].

Agelink presented in his comment lgCV data on eight patients before and during clozapine medication. Their data and ours demonstrate a substantial decrease of lgCV in 7 of 8 patients under early treatment (100 mg of clozapine). The inconsistent further decrease of lgCV during further increasing clozapine doses is remarkable. This finding is open for discussion. Agelink et al. point out that there is no linear correlation between higher dosages and a further decrease in lgCV. An adaptation to the m2 receptor block could be important, as well as disease-related changes of ANS function.

Our statements on low-frequency (LF) band and sympathetic outflow are still preliminary, gathered within a short time period and without standing and Valsalva maneuver. As discussed in our paper, clozapine-induced increase of catecholamines in plasma and CSF is not incompatible with a decrease of power in the LF band. We are quite aware of the complex regulation of slow oscillations as proposed by Kingwell’s group [2].

We suppose that the cheap and broadly available use of the ECG trace from digital routine EEGs will probably help us to monitor at least the individual anticholinergic properties of several psychotropic drugs over several time points in hundreds of patients to illuminate open questions such as neuroadaptation. The knowledge about drug effects on the ECG should spread from the few departments that have a neurocardiac laboratory to the hundreds of psychiatry departments with a digital EEG.

References

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• 2 Kingwell B A, Thompson J M, Kaye D M, McPherson G A, Jennings G L, Esler M D. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure.  Circulation. 1994;  90 234-240
• 3 Rechlin T. Decreased R-R variation: a criterium for overdosage of tricyclic psychotropic drugs.  Intensive Care Med.. 1995;  21 598-601
• 4 Rechlin T, Weis M, Claus D. Heart rate variability in depressed patients and differential effects of paroxetine and amitriptyline on cardiovascular autonomic functions.  Pharmacopsychiatry. 1994;  27 124-128
• 5 Rechlin T, Weis M, Claus D, Kaschka W P. Identifying delirious states and autonomic cardiovascular dysfunction associated with amitriptyline treatment by standardized analysis of heart rate.  Psychiatry Res.. 1995;  56 279-287
• 6 Vogel L R, Muskin P R, Collins E D, Sloan R P. Lorazepam reduces cardiac vagal modulation in normal subjects.  J Clin Psychopharmacol. 1996;  16 449-453

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